The overall purpose of this proposal is to investigate the c-Rel proto- oncogene function in antigen-receptor-mediated proliferation and apoptosis in B lymphocytes. Although the intracellular signaling pathways of B cell antigen receptor have been examined extensively, the molecular mechanisms leading to cell cycle progression and apoptosis are largely unknown. C-Rel is a member of the NF-kappaB/Rel family of transcription factors that respond to antigen receptor signals. Being a proto-oncogene, c-Rel is strongly linked to lymphoid tumorigenesis in both human and avian. To facilitate the studies of c-Rel in immune regulation and tumorigenesis, we have generated the c-Rel knockout mice using a gene targeting approach. Both B and T lymphocytes derived from the c-Rel knockout mice are defective in proliferative responses induced by antigen receptor and various mitogens. In this proposal, we plan to (1) determine the stage of cell cycle that is dependent upon c-Rel activity, (2) identify the target gene defect(s) in the c-Rel knockout B lymphocytes, and (3) address the in vivo role of c-Rel in humoral immune responses and immune tolerance. Using the c-Rel knockout mice generated in our laboratory, we are ideally positioned to unravel the molecular events of antigen receptor-mediated cell cycle progression in B lymphocytes, as well as to define c-Rel function in immune response and tolerance. A better understanding of the mechanisms governing lymphocyte proliferation and apoptosis provides a rationale for the development of potential therapeutic procedures to cure or prevent immune disorders, such as immunodeficiencies and autoimmunity.